Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis.

Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PIMZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PIZZ). Recent genetic data suggest that the PIMZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PIZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PIMZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PIMZ individuals. Here, we discuss the limited data on the PIMZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PIMZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.